Schering Corp. is developing a thrombin receptor antagonist (“TRA”) for use in a variety of cardiovascular applications, including treatment of acute coronary syndrome (“ACS”) and secondary prevention. The active pharmaceutical ingredient (“API”), SCH 530348, has completed phase I and II clinical trials, and is currently in phase III trials. The development of an understanding of the metabolism of SCH 530348 is both a desirable progression in the science and a necessary step in the commercialization of this thrombin receptor antagonist.
Thrombin is known to have a variety of activities in different cell types and thrombin receptors are known to be present in such cell types as human platelets, vascular smooth muscle cells, endothelial cells and fibroblasts. It is therefore possible that thrombin receptor antagonists, also known as protease activated receptor (PAR) antagonists, will be useful in the treatment of thrombotic, inflammatory, atherosclerotic and fibroproliferative disorders, as well as other disorders in which thrombin and its receptor play a pathological role.
U.S. Pat. No. 7,304,078 discloses a genus of compounds, including a specific thrombin receptor antagonist compound identified as Example 2, herein identified as SCH 530348. SCH 530348 has the following structure:
and the following chemical formula: Ethyl[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(E)-2-[5-(3-fluorophenyl)-2-pyridinyl]ethenyl]dodecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-6-yl]carbamate. SCH 530348 exhibits good thrombin receptor antagonist activity (potency) and selectivity, and is currently in development by Schering Corp. Co-pending U.S. patent application Ser. No. 10/705,282, herein incorporated by reference, discloses a variety of indications and combination formulations for thrombin receptor antagonists including SCH 530348. A preferred crystalline form of the bisulfate salt of SCH 530348 is disclosed in U.S. Pat. No. 7,235,567. U.S. patent application Ser. Nos. 11/771,571; 11/771,520; and 11,860,165 disclose capsule formulations, tablet formulations and lyophilized formulations (respectively) of SCH 530348, and methods of treating various conditions by administering same.
The use of a small subset of thrombin receptor antagonists to treat a variety of conditions and diseases is disclosed in U.S. publication no. 04/0192753. The prevention of complications associated with cardiopulmonary bypass surgery by administration of a thrombin receptor antagonist is taught in U.S. application Ser. No. 11/613,450. Methods of preventing cardiac events after percutaneous intervention (“PCI,” e.g., angioplasty, stent introduction) are disclosed in U.S. application Ser. No. 12/051,504. Substituted thrombin receptor antagonists are disclosed in U.S. Pat. Nos. 6,063,847; 6,326,380; and 6,645,987 and U.S. publication nos. 03/0203927; 04/0216437A1; 04/0152736; and 03/0216437. All of the herein cited references are incorporated in their entirety.
It would be beneficial to identify any active metabolites of SCH 530348 that persist in the body after dosing. The invention seeks to provide these and other benefits, which will become apparent as the description progresses.